Proteins and polypeptides are minimally absorbed from the adult mammalian intestinal tract. The oral delivery of protein and polypeptide drugs is further complicated by the presence of proteolytic digestive enzymes in the stomach and intestines. Unprotected proteins which are administered orally are largely degraded by such enzymes before they are able to pass through the enteric wall and enter blood circulation. While many of these proteins can be successfully delivered by intravascular or intramuscular injection, such delivery routes suffer from low patient acceptability, particularly when the drugs must be administered on a regular basis by self-injection. Control of the delivery rate and frequency by this route is, in most cases, only possible in a hospital setting.
In order to avoid the need for injection, many approaches for modifying and protecting protein drugs against proteolytic degradation have been proposed. Of particular interest to the present invention, it has been proposed that proteins be incorporated into polymeric particles which resist proteolytic degradation when passing through the stomach and intestines and which are sufficiently small to pass through the intestinal mucosa to effect systemic delivery. While promising, the use of such "nanoparticles" suffers from certain disadvantages. In fact, it has been shown by many authors and for particles of different compositions that only a small fraction is allowed to pass into the systemic circulation and that most nanoparticles are excreted. Thus, nanoparticle carriers per se do not significantly enhance the absorption of the drug.
For these reasons, it would be desirable to provide improved compositions and methods for the oral administration and systemic delivery of polypeptide drugs. It would be particularly desirable to provide improved compositions which, in addition to protecting the drug being delivered, are able to target the protected drug to the intestinal mucosa to enhance the delivery rate of the drug and increase the residence time of the drug and particular carrier in the intestines. It would be especially desirable to provide improved compositions exhibiting the ability to induce the uptake of the drug carrier into the mucosal cell to increase the amount of drug delivered across the intestinal mucosa.
The use of nanoparticles for the oral delivery of insulin is described in Michel et al. (1991) J. Pharm. Pharmacol. 43:1-5, and Damge et al. (1988) Diabetes 37:246-251. Dougan et al. (1990) Biochem. Soc. Trans. 18:746-748 suggests that invasins "may prove to be useful tools for studying methods for introducing drugs into cells." Invasins are surface proteins present on certain pathogenic bacteria. Invasins bind to integrins present on epithelial and other cells, mediating entry of the bacteria into the cell. Integrins are adhesion receptors whose normal function is to bind to extracellular matrices, such as fibronectin. Fibronectin and other cellular matrices include conserved recognition sites, such as arginine-glycine-aspartic acid (RGD), which bind to cell surface integrins (Ruoslahti and Pierschbacher (1987) Science 238:491-497; and Mueller et al. (1989) J. Cell Biol. 109:3455-3464). The relationship between invasins and integrins is described in a number of references, including Isberg (1989) Mol. Microbiol. 3:1449-1453; Isberg (1990) Mol. Biol. Med. 7:73-82; Isberg and Leong (1990) Cell 60:861-871; and Leong et al. (1991) Infect. Immun. 59:3424-3433. Fibronectin-coated latex beads have been shown to be phagocytosed by cultured fibroblasts (McKeown et al. (1990) Cell Tissue Res. 523-530). Adhesion molecules derived from bacteria have been purified and attached to particles as a model for drugs having controlled transit time through the intestines (WO 90/04963); however, these adhesion molecules have not been shown to promote endocytosis or phagocytosis.